ABSTRACT The rapid rise in the use and misuse of prescription opioids in the United States extends to pregnant women. Recent data from our group suggests that 22% of Medicaid beneficiaries and 14% of commercial insurance beneficiaries are exposed to opioids during pregnancy, including up to 10% during the first trimester. Despite the high prevalence of exposure to prescription opioids, little is known about the impact on adverse pregnancy outcomes. Epidemiological and pre-clinical data suggests that such exposure may be associated with higher risk of certain congenital malformations, preterm delivery, small for gestational age, and ischemic placental complications. But data are few and conflicting, and the available literature is limited by concerns related to recall bias, residual confounding bias, and small sample size. Evaluating the impact of prescription opioids using observational data is challenging due to concerns related to potential exposure misclassification due to illicit use and diversion, confounding by indication, and missing information on other relevant confounders. In this study we will utilize innovative, state of the art epidemiological methods to overcome these challenges, generating unbiased or minimally biased estimates of the risk to pregnancy outcomes of exposure to commonly used prescription opioids during etiologically relevant periods of gestation. Specific methods that we intend to employ include high-dimensional propensity score adjustment, propensity score calibration, alternative referents (including sibling and discontinuer comparisons), livebirths sensitivity analyses, propensity score fine stratification, and bias analyses to account for potential misclassification of exposure and outcome. The primary goal of the study is to define the biological effects associated with prescription opioid exposure, independent of confounding factors, which will therefore be relevant to both medical and non- medical use of prescription opioids during pregnancy. To accomplish this, we will use a cohort of 1.8 million pregnancies of Medicaid beneficiaries and a cohort of 1.7 million pregnancies of commercial insurance beneficiaries. We will evaluate the association between prescription opioid exposure during the etiologically relevant window and a variety of important adverse pregnancy outcomes previously hypothesized to be associated with such exposure. We will also assess for the outcomes in relation to specific opioids and will assess the impact of duration of exposure and dose. The results of the studies will have an important and direct clinical impact. Understanding the safety of prescription opioid exposure during pregnancy will guide clinicians' approach to the treatment of pain in pregnancy, will inform the counseling of women who misuse prescription opioids during pregnancy, and will guide the clinical management of opioid exposed women and their offspring.